Obesity (body mass index, BMI >30) afflicts millions of people in the United States and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke, hypertension, and morbidity. In industrialized countries, the problem of obesity is compounded by overeating, a high fat content diet, and a lack of exercise. The last few years have seen the characterization of over 30 neuroendocrine pathways that have been identified to regulate energy homeostasis. The melanocortin pathway includes six such genetic factors that have been demonstrated to mediate weight homeostasis. The melanocortin pathway includes the melanocortin agonists, derived from the preprohormone proopiomelanocortin (POMC) gene transcript, the five G-protein coupled (GPCR) melanocortin receptors identified to date (MC1R-MC5R), and the only two known endogenous antagonists of GPCRs, agouti (ASP) and agouti-related protein (AGRP) known to date. In 2007, endogenous &#946;-defensin peptides have also been reported to participate in the melanocortin pathway. The six melanocortin genetic factors that have been identified as being involved in energy homeostasis are the POMC, ASP, AGRP, the brain melanocortin-4 receptor (MC4R), the melanocortin-3 receptor (MC3R), and the &#946;- defensin peptide CB103 proteins. These data support the hypothesis that the melanocortin pathway is involved in the complex behavior of feeding and energy homeostasis. This project is focused upon identifying MC3R selective ligands, discerning putative MC3R ligand-receptor interactions and understanding the basic science aspect of GPCR molecular recognition and differentiation of agonist and antagonist mechanisms. Additionally, using the tools in hand that have been discovered through the previous research on this project, we propose to study the role of the MC3R in energy homeostasis.